Androgenic alopecia (i.e. male pattern baldness) poses serious psycho-social issues for millions of effected individuals. These individuals include 54% of all US men aged 30 or more and 50 to 75% of US women over the age of 65. Otberg, N., et al., Androgenetic alopecia, Endocrinology and metabolism clinics of North America, 2007 June, 36(2), 379-398 and Scheinfeld, N., A review of hormonal therapy for female pattern (androgenic) alopecia, Dermatology online journal, 2008. 14(3), 1-5. This translates to more than 150 million individuals in the US alone.
The pathophysiology of androgenic alopecia is not well understood, but as the name implies, testosterone plays a key role in male pattern baldness and hair loss. This role was inferred from the finding that castrated men do not suffer from hair loss. Otberg et al., 2007. Similarly, pseudohermaphrodites that are null at the 5-alpha reductase (“5-AR”) loci, which encode for an enzyme involved in testosterone metabolism, are also protected from androgenic alopecia. Ellis J. A., et al., Male pattern baldness: current treatments, future prospects, Drug Discovery Today, 2008, 13, 791-797. Testosterone, a lipophilic molecule that diffuses the cell membrane, is converted into its more active form, dihydrotestosterone (“DHT”), by cytoplasmic 5-AR. There are two types of 5-AR, 1 and 2, with type 2 5-AR found in the skin and the inner root sheath of hair follicles. Burkhart C. G., et al., 5 alpha-reductase and finasteride in pattern alopecia and acne, Journal of Drugs in Dermatology, 2004, 3, 363-364. Once DHT enters the nucleus it binds to the androgen receptor, regulating gene expression. However, the genes involved in mediating male pattern baldness have yet to be identified.
Only minoxidil, a topically applied compound, and finasteride, an oral medication, have been approved to treat androgenic alopecia. Minoxidil was originally developed as a systemic vasodilating agent to treat hypertension, however many patients suffered with disseminated hypertrichosis as a result of treatment. Bienova M., et al, Androgenetic alopecia and current methods of treatment, Acta Dermatovenerologica Alpina, Pannonica, et Adriatica, 2005, 14, 5-8. It was soon discovered that topical application of minoxidil results in limited hair restoration, largely confined to the sites of application. Analysis of the cellular and molecular mechanisms of minoxidil-mediated hair growth has shown that it promotes the survival of dermal papilla cells (“DPCs”) of human hair follicles, by activating both ERK and Akt and by preventing cell death by increasing the ratio of Bcl-2/Bax. Han J. H., et al., Effect of minoxidil on proliferation and apoptosis in dermal papilla cells of human hair follicle, J Dermatol Sci, 2004, 34, 91-98. The DPCs are thought to provide trophic support to the hair follicle. Rendl M., et al., BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties, Genes Dev 2008, 22, 543-557. Among the proteins up-regulated by minoxidil are the trophic factors vascular endothelial growth factor (“VEGF”), hepatocyte growth factor (“HGF”), insulin-like growth factor 1(“IGF-1”) and bone morphogenic protein 4 (“BMP-4”). Ryu S. et al., Mycophenolate antagonizes IFN-gamma-induced catagen-like changes via beta-catenin activation in human dermal papilla cells and hair follicles, International Journal of Molecular Sciences 2014, 15, 16800-16815. Further, minoxidil is known to potentiate HGF and IGF-1 actions through the activation of uncoupled sulfonylurea receptor (“SUR”) on the plasma membrane of DPCs. Minoxidil has been shown to be effective in maintaining existing hair follicles, but ineffective in stimulating new follicles. Sinclair has shown that only 15% of those treated with minoxidil had new hair growth, while 50% of those treated maintained existing hair, with no additional loss at 6-months. Sinclair R., Male pattern androgenetic alopecia, BMJ, 1998, 317, 865-869. Notably, discontinuation of minoxidil treatment results in the resumption of hair loss, presumably through the loss of trophic support.
Finasteride, unlike minoxidil, is an oral medication, with potentially severe side effects including erectile dysfunction, gynecomastia, and loss of libido. Finasteride is a competitive 5-AR inhibitor that inhibits the conversion of testosterone to DHT, resulting in a decrease in androgenic alopecia. Price V. H., Treatment of hair loss, The New England Journal of Medicine, 1999, 341, 964-973.
In addition to minoxidil and finasteride, cyclosporine A (“CSA”), an immunosuppressive drug intended to prevent rejection of solid organ allografts, promotes robust hair growth in up to 80% of transplant patients receiving systemic treatment. Wysocki G. P., et al., Hypertrichosis in patients receiving cyclosporine therapy, Clin Exp Dermatol, 1987, 12, 191-196. While CSA is highly effective in preventing graft rejection, it has severe and undesirable side effects when taken orally or parenterally. Thus, CSA is a poor choice for systemic administration in all but the most life threatening situations. In contrast, the topical administration of low-dose, topical CSA is not associated with immune suppression, hypertension, renal toxicity or the other severe or life-threatening side effects seen with oral CSA administration.
The mechanism of CSA-mediated hair growth was recently elucidated by Fuchs and her colleagues. These workers demonstrated that NFATc1 is expressed preferentially by the follicular stem cell, where it acts to repress stem cell proliferation. Upon administration, CSA binds to the calmodulin-dependent, serine/threonine protein phosphatase calcineurin, which in turn binds to NFAT, and relieves the repression on the follicular stem cell. With the NFAT repression relieved, the follicular stem cells proliferate, resulting in precocious follicular growth. Horsley V., et al., NFATc1 balances quiescence and proliferation of skin stem cells, Cell, 2008, 132, 299-310. Interestingly, as opposed to oral administration, topical treatment with CSA has shown to be very inefficient at promoting hair growth in androgenic alopecia when used alone, or in combination with minoxidil. Gilhar A., et al., Topical cyclosporine in male pattern alopecia, J Am Acad Dermatol, 1990, 22, 251-253; Buhl A. E., et al., Differences in activity of minoxidil and cyclosporin A on hair growth in nude and normal mice. Comparisons of in vivo and in vitro studies, Laboratory Investigation; A Journal of Technical Methods and Pathology, 1990, 62, 104-107.
Another compound that has shown hair growth stimulation is RT175 (AMG-474-00, GM1485, GPI 1485). RT175 is a 241 Dalton molecule having the following chemical structure
RT175 has been shown to re-grow hair in rats that have undergone craniotomy prior to neurosurgery. Ducruet et al., GM1485, a nonimmunosuppressive immunophilin ligand, promotes neurofunctional improvement and neural regeneration following stroke, J Neurosci Res, 2012 July, 90(7):1413-23. RT175 has also been shown to induce hair growth in shaved mice. European Patent No. 1842845 to GliaMed, Inc., published Oct. 10, 2007. RT175 binds with high affinity to FK506 binding protein 4 (“FKBP52”). FKBP52 is known to act as a molecular chaperone for the glucocorticoid receptor (“GR”). After binding to ligand, the RT175/GR complex translocates to the nucleus. Banerjee A., et al. Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins, Biochemistry, 2008, 47, 10471-10480. It has been shown that that RT175 treatment of fibroblasts for 2 hours results in the translocation of FKBP52 to the nucleus, presumably with its cargo. This timeframe is consistent with cDNA array studies that have shown a significant upregulation of chromatin remodeling via the transcription factors Ikaros and Afq1, suggesting that treatment with RT175 results in alteration in chromatin structure as the cells are reprogrammed, including the up-regulation of secreted molecules that are associated with hair growth, wnt1 and IGF2. Keshava C., et al., Transcriptional signatures of environmentally relevant exposures in normal human mammary epithelial cells: benzo[a]pyrene, Cancer Letters, 2005, 221, 201-211; Koipally J., et al. Ikaros chromatin remodeling complexes in the control of differentiation of the hemo-lymphoid system, Cold Spring Harb Symp Quant Biol 1999, 64, 79-86; Galbiati F., et al., Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains, J Biol Chem, 2000, 275, 23368-23377; Tamimi Y. et al., WNT5A is regulated by PAX2 and may be involved in blastemal predominant Wilms tumorigenesis, Neoplasia, 2008, 10, 1470-1480; Nakao K., et al., IGF2 modulates the microenvironment for osteoclastogenesis, Biochem Biophys Res Commun, 2009, 378, 462-466; Sun Y., et al., Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiation, PLoS ONE, 2008, 3, e3406; Andl T., et al., WNT signals are required for the initiation of hair follicle development, Developmental Cell, 2002, 2, 643-653.
Despite the commercial availability of minoxidil and finasteride and demonstrations of hair growth following systemic administration of cyclosporine A and topical administration of RT175 in rodents there remains a need in the art for a topical composition for the treatment of alopecia in humans that avoids the side effects of oral or parenteral administration and is long-lasting.